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BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04327206
Recruitment Status : Recruiting
First Posted : March 31, 2020
Last Update Posted : July 8, 2020
Sponsor:
Collaborator:
Royal Children's Hospital
Information provided by (Responsible Party):
Murdoch Childrens Research Institute

Brief Summary:
Phase III, two-group multicentre, randomised controlled trial in up to 10 078 healthcare workers to determine if BCG vaccination reduces the incidence and severity of COVID-19 during the 2020 pandemic.

Condition or disease Intervention/treatment Phase
Coronavirus Disease 2019 (COVID-19) Respiratory Illness Corona Virus Infection COVID-19 Drug: BCG Vaccine Drug: 0.9%NaCl Phase 3

Detailed Description:

Healthcare workers are at the frontline of the coronavirus disease (COVID-19) pandemic. They will be randomised to receive a single dose of BCG vaccine or 0.9% NaCl placebo. Participants will be followed-up for 12 months with notification from a Smartphone application (up to daily when ill) and surveys to identify and detail COVID-19 infection. Additional information on severe disease will be obtained from hospital medical records and/or government databases. Blood samples will be collected prior to randomisation and at 3 and 12 months to determine exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Where required, swab/blood samples will be taken at illness episodes to assess SARS-CoV-2 infection.

The trial includes a pre-planned meta-analysis with data from 2834 participants recruited in the first phase of this study, where participants were randomised to receive BCG or no BCG vaccine at the time of receiving influenza vaccination.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10078 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Phase III, two group, multicentre, randomised controlled trial
Masking: Double (Participant, Outcomes Assessor)
Masking Description: The control group will receive a placebo of 0.9% sodium chloride (NaCl). Members of the research team doing the follow-up of participants and analysis will be blinded to the group allocation (by the removal of this variable and all other variables related to BCG from the dataset) until the formal detailed statistical analysis plan is confirmed and signed by all investigators and all data cleaning/preparation is complete.
Primary Purpose: Prevention
Official Title: BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers Following Coronavirus Exposure (BRACE) Trial
Actual Study Start Date : March 30, 2020
Estimated Primary Completion Date : October 30, 2020
Estimated Study Completion Date : March 30, 2022


Arm Intervention/treatment
Experimental: BCG vaccine
Participants will receive a single dose of BCG vaccine (BCG-Denmark). The adult dose of BCG vaccine is 0.1 mL injected intradermally over the distal insertion of the deltoid muscle onto the humerus (approximately one third down the upper arm).
Drug: BCG Vaccine

Freeze-dried powder: Live attenuated strain of Mycobacterium bovis (BCG), Danish strain 1331.

Each 0.1 ml vaccine contains between 200000 to 800000 colony forming units. Adult dose is 0.1 ml given by intradermal injection

Other Names:
  • Bacille Calmette-Guerin Vaccine
  • Bacillus Calmette-Guerin Vaccine
  • Statens Serum Institute BCG vaccine
  • Mycobacterium bovis BCG (Bacille Calmette Guérin), Danish Strain 1331
  • BCG Denmark

Placebo Comparator: 0.9% Saline
Participants will receive a single 0.1 mL dose of 0.9%NaCl injected intradermally over the distal insertion of the deltoid muscle onto the humerus (approximately one third down the upper arm).
Drug: 0.9%NaCl
0.9% Sodium Chloride Injection
Other Name: 0.9% Saline




Primary Outcome Measures :
  1. COVID-19 disease incidence [ Time Frame: Measured over the 6 months following randomisation ]

    Number of participants with COVID-19 disease defined as

    • positive SARS-Cov-2 test (PCR or serology), plus
    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)

  2. Severe COVID-19 disease incidence [ Time Frame: Measured over the 6 months following randomisation ]

    Number of participants with severe COVID-19 disease, defined as: COVID-19 disease with hospitalisation, death, or non-hospitalised severe disease.

    Non-hospitalised severe disease is defined as non-ambulant (*) for ≥ 3 consecutive days OR unable to work (**) for ≥ 3 consecutive days.

    (*) "pretty much confined to bed (meaning finding it very difficult to do any normal daily activities".

    (**) "I do not feel physically well enough to go to work"



Secondary Outcome Measures :
  1. COVID-19 incidence by 12 months [ Time Frame: Measured over the 12 months following randomisation ]

    Number of participants with COVID-19 disease defined as

    • positive SARS-Cov-2 test (PCR or serology), plus
    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)

  2. Severe COVID-19 incidence by 12 months [ Time Frame: Measured over the 12 months following randomisation ]

    Number of participants with severe COVID-19 disease, defined as: COVID-19 disease with hospitalisation, death, or non-hospitalised severe disease.

    Non-hospitalised severe disease is defined as non-ambulant(*) for ≥ 3 consecutive days OR unable to work (**) for ≥ 3 consecutive days.

    * "pretty much confined to bed (meaning finding it very difficult to do any normal daily activities"

    ** "I do not feel physically well enough to go to work"


  3. Time to first symptom of COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]

    Time to first symptom of COVID-19 in a participant who subsequently meets the case definition:

    • positive SARS-Cov-2 test (PCR or serology), plus
    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)

  4. Episodes of COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]

    Number of episodes of COVID-19 disease defined as

    • positive SARS-Cov-2 test (PCR or serology), plus
    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)

  5. Asymptomatic SARS-CoV-2 infection [ Time Frame: Measured over the 12 months following randomisation ]

    Number of participants with asymptomatic SARS-CoV-2 infection defined as

    • Evidence of SARS-CoV-2 infection (by PCR or seroconversion)
    • Absence of respiratory illness (using self-reported questionnaire)
    • No evidence of exposure prior to randomisation (inclusion serology negative)

  6. Work absenteeism due to COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days (using self-reported questionnaire) unable to work (excludes quarantine/workplace restrictions) due to COVID-19 disease defined as

    • positive SARS-Cov-2 test (PCR or serology), plus
    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)

  7. Bed confinement due to COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days confined to bed (using self-reported questionnaire) due to COVID-19 disease defined as

    • positive SARS-Cov-2 test (PCR or serology), plus
    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)

  8. Symptom duration of COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days with symptoms in any episode of illness that meets the case definition for COVID-19 disease:

    • positive SARS-Cov-2 test (PCR or serology), plus
    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure (using self-reported questionnaire)

  9. SARS-CoV-2 pneumonia [ Time Frame: Measured over the 12 months following randomisation ]
    Number of pneumonia cases (abnormal chest X-ray) (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test

  10. Oxygen therapy with SARS-CoV-2 [ Time Frame: Measured over the 12 months following randomisation ]
    Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test

  11. Critical care admissions with SARS-CoV-2 [ Time Frame: Measured over the 12 months following randomisation ]
    Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test

  12. Critical care admission duration with SARS-CoV-2 [ Time Frame: Measured over the 12 months following randomisation ]
    Number of days admitted to critical care (using self-reported questionnaire and/or medical/hospital records) associated with a positive SARS-CoV-2 test

  13. Mechanical ventilation with SARS-CoV-2 [ Time Frame: Measured over the 12 months following randomisation ]
    Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records) and a positive SARS-CoV-2 test

  14. Mechanical ventilation duration with SARS-CoV-2 [ Time Frame: Measured over the 12 months following randomisation ]
    Number of days that participants needed mechanical ventilation (using self-reported questionnaire and/or medical/hospital records) and a positive SARS-CoV-2 test

  15. Hospitalisation duration with COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]
    Number of days of hospitalisation due to COVID-19 (using self-reported questionnaire and/or medical/hospital records).

  16. Mortality with SARS-CoV-2 [ Time Frame: Measured over the 12 months following randomisation ]
    Number of deaths (from death registry) associated with a positive SARS-CoV-2 test

  17. Fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of participants with fever or respiratory illness will be defined as:

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)

  18. Episodes of fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of episodes of fever or respiratory illness, defined as

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)

  19. Work absenteeism due to fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days (using self-reported questionnaire) unable to work (excludes quarantine/workplace restrictions) due to fever or respiratory illness defined as

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)

  20. Bed confinement due to fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days confined to bed (using self-reported questionnaire) due to fever or respiratory illness defined as

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)

  21. Symptom duration of fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]

    Number of days with symptoms in any episode of illness that meets the case definition for fever or respiratory illness:

    • fever (using self-reported questionnaire), or
    • at least one sign or symptom of respiratory disease including cough, shortness of breath, respiratory distress/failure, runny/blocked nose (using self-reported questionnaire)

  22. Pneumonia [ Time Frame: Measured over the 12 months following randomisation ]
    Number of pneumonia cases (abnormal chest X-ray) (using self-reported questionnaire and/or medical/hospital records)

  23. Oxygen therapy [ Time Frame: Measured over the 12 months following randomisation ]
    Need for oxygen therapy (using self-reported questionnaire and/or medical/hospital records)

  24. Critical care admissions [ Time Frame: Measured over the 12 months following randomisation ]
    Number of admission to critical care (using self-reported questionnaire and/or medical/hospital records)

  25. Mechanical ventilation [ Time Frame: Measured over the 12 months following randomisation ]
    Number of participants needing mechanical ventilation (using self-reported questionnaire and/or medical/hospital records)

  26. Mortality [ Time Frame: Measured over the 12 months following randomisation ]
    Number of deaths (from death registry)

  27. Hospitalisation duration with fever or respiratory illness [ Time Frame: Measured over the 12 months following randomisation ]
    Number of days of hospitalisation due to fever or respiratory illness (using self-reported questionnaire, medical/hospital records and/or government registries)

  28. Unplanned work absenteeism [ Time Frame: Measured over the 12 months following randomisation ]
    Number of days of unplanned absenteeism for any reason (using self-reported questionnaire)

  29. Hospitalisation cost to treat COVID-19 [ Time Frame: Measured over the 12 months following randomisation ]
    Cost of hospitalisation due to COVID-19 will be reported and compared between groups (using hospital administrative linked costing records held by individual hospitals and state government routine costing data collections to provide an estimate of the cost to hospitals for each episode of COVID-19 care)

  30. Local and systemic adverse events to BCG vaccination in healthcare workers [ Time Frame: Measured over the 3 months following randomisation ]
    Type and severity of local and systemic adverse events will be collected in self-reported questionnaire and graded using toxicity grading scale.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Over 18 years of age
  • In Europe: Healthcare worker who over the next few months of COVID-19 pandemic will be working onsite in patient areas or having face-to-face contact with patients.

    -Note that this may include staff in either hospitals or other patient care facilities, such as nursing homes. Proof of registration as patient care worker will be required at enrolment.

  • In Australia: Employed by one of the hospitals involved in the study

    - Note that this is not restricted to clinicians or nurses and include all individuals who work within the participating hospital during the COVID-19 outbreak.

  • Provide a signed and dated informed consent form
  • Has received the influenza vaccine at least 72 hours prior to randomisation

    - Note that this criteria only applies in to Australian participants

  • Pre-randomisation blood collected

Exclusion Criteria:

  • Has any BCG vaccine contraindication
  • Fever or generalised skin infection (where feasible, randomisation can be delayed until cleared)
  • Weakened resistance toward infections due to a disease in/of the immune system
  • Receiving medical treatment that affects the immune response or other immunosuppressive therapy in the last year. These therapies include systemic corticosteroids (more than or equal to 20 mg for more than or equal to 2 weeks), non-biological immunosuppressant (also known as 'DMARDS'), biological agents (such as monoclonal antibodies against tumour necrosis factor (TNF)-alpha).
  • Has a congenital cellular immunodeficiency, including specific deficiencies of the interferon-gamma pathway
  • Has a malignancy involving bone marrow or lymphoid systems
  • Has any serious underlying illness (such as malignancy). Please note: People with cardiovascular disease, hypertension, diabetes, and/or chronic respiratory disease are eligible if not immunocompromised
  • Known or suspected HIV infection, even if asymptomatic or has normal immune function. This is because of the risk of disseminated BCG infection
  • Has active skin disease such as eczema, dermatitis or psoriasis at or near the site of vaccination. A different site (other than left arm) can be chosen if necessary
  • Pregnant Although there is no evidence that BCG vaccination is harmful during pregnancy, it is a contra-indication to BCG vaccination. Therefore, we will exclude women who think they could be pregnant.
  • Another live vaccine administered in the month prior to randomisation
  • Require another live vaccine to be administered within the month following BCG randomisation If the other live vaccine can be given on the same day, this exclusion criteria does not apply
  • Known anaphylactic reaction to any of the ingredient present in the BCG vaccine
  • Previous active tuberculosis (TB) disease
  • Previous adverse reaction to BCG vaccine (significant local reaction (abscess) or suppurative lymphadenitis)
  • BCG vaccine given within the last year
  • Has previously had a SARS-CoV-2 positive test result
  • Already part of this trial, recruited at a different hospital
  • Participation in another COVID-19 prevention trial

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04327206


Contacts
Layout table for location contacts
Contact: Prof Nigel Curtis, MBBS PhD +613 93456366 nigel.curtis@rch.org.au
Contact: Kaya Gardiner +613 99366461 kaya.gardiner@mcri.edu.au

Locations
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Australia, New South Wales
St Vincent's Hospital, Sydney Not yet recruiting
Sydney, New South Wales, Australia, 2010
Contact: Dr Anthony Byrne, MBBS PhD    +61 2 8382 1111    anthony.byrne@svha.org.au   
Prince of Wales Hospital Not yet recruiting
Sydney, New South Wales, Australia, 2031
Contact: A/Prof Jeffrey Post, MBBS PhD    +61 2 93823405      
Sydney Children's Hospital, Randwick Not yet recruiting
Sydney, New South Wales, Australia, 2145
Contact: Dr Brendan McMullan, BMed, FRACP    +61 2 9382 1111    brendan.mcmullan@health.nsw.gov.au   
The Children's Hospital at Westmead Recruiting
Sydney, New South Wales, Australia, 2145
Contact: A/Prof Nicholas Wood, MBBS PhD    +61 2 9845 0000    nicholas.wood@health.nsw.gov.au   
Westmead Hospital Not yet recruiting
Sydney, New South Wales, Australia, 2145
Contact: A/Prof Mark Douglas, MBBS PhD    +61 2 8890 6012    mark.douglas@sydney.edu.au   
Australia, South Australia
Royal Adelaide Hospital Recruiting
Adelaide, South Australia, Australia, 5000
Contact: Dr Simone Barry, MBBS PhD    +61 8 7074 0000    simone.barry@sa.gov.au   
South Australian Health and Medical Research Institute Recruiting
Adelaide, South Australia, Australia, 5001
Contact: Prof David Lynn, PhD    +61 8 8128 4053    david.lynn@sahmri.com   
Women's and Children's Hospital Recruiting
North Adelaide, South Australia, Australia, 5006
Contact: Prof Helen Marshall, MBBS MD MPH    +61 8 8161 8115    helen.marshall@adelaide.edu.au   
Australia, Victoria
Epworth Victoria Parade Active, not recruiting
Melbourne, Victoria, Australia, 3002
Royal Children's Hospital Active, not recruiting
Melbourne, Victoria, Australia, 3052
Epworth Richmond Active, not recruiting
Melbourne, Victoria, Australia, 3121
Epworth Eastern Active, not recruiting
Melbourne, Victoria, Australia, 3128
Monash Health- Monash Medical Centre Active, not recruiting
Melbourne, Victoria, Australia, 3168
Australia, Western Australia
Fiona Stanley Hospital Active, not recruiting
Murdoch, Western Australia, Australia, 6150
Perth Children's Hospital Active, not recruiting
Perth, Western Australia, Australia, 6009
Sir Charles Gairdner Hospital Active, not recruiting
Perth, Western Australia, Australia, 6009
Sponsors and Collaborators
Murdoch Childrens Research Institute
Royal Children's Hospital
Investigators
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Principal Investigator: Prof Nigel Curtis Murdoch Children's Research Institute
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Responsible Party: Murdoch Childrens Research Institute
ClinicalTrials.gov Identifier: NCT04327206    
Other Study ID Numbers: 62586
First Posted: March 31, 2020    Key Record Dates
Last Update Posted: July 8, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Beginning 6 months following analysis and article publications, the following may be made available long-term for use by future researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept MCRI's conditions, under a collaborator agreement, for accessing:

  • Individual participant data that underlie the results reported in our articles after de-identification (text, tables, figures and appendices)
  • Study protocol, Statistical Analysis Plan, Participant Informed Consent Form (PICF)
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: Beginning 6 months following analysis and article publications, for long-term use
Access Criteria: Researchers from a recognised research institution whose proposed use of the data has been ethically reviewed and approved by an independent committee and who accept MCRI's conditions, under a collaborator agreement

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Coronavirus Infections
Severe Acute Respiratory Syndrome
Virus Diseases
Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Respiratory Tract Infections
Respiratory Tract Diseases
Vaccines
BCG Vaccine
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic